Sepsis-induced cardiac dysfunction

Abstract

Sepsis, severe sepsis and septic shock represent increasingly grave stages of the systemic inflammatory response to severe infection. Affected patients have a high mortality and morbidity, predominantly as a consequence of multiple organ failure. Cardiac dysfunction with impaired left-ventricular ejection fraction is a well-described manifestation of this syndrome and can be diagnosed in up to 60% of patients with septic shock. The three original articles of this cumulative habilitation describe the cardiac and haemodynamic alterations in septic patients. The review article summarises underlying mechanisms of sepsis-induced cardiac dysfunction. In study 1, B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) levels were measured in 24 patients with severe sepsis or septic shock and 51 patients with acute heart failure. We showed, that in patients with severe sepsis or septic shock, BNP and NT-proBNP values were highly elevated and, despite significant haemodynamic differences, comparable with those found in acute heart failure patients. This supported previous studies, which attributed elevated BNP levels to sepsis-induced myocardial dysfunction. Twelve haemodyamic unstable patients, all monitored with a pulmonary artery catheter, were included in study 2. Despite significant differences in cardiac index and troponin T plasma level, BNP and NTproBNP levels did not differ significantly between the patients with sepsis and acute heart failure. Within patient, changes in BNP and NT-proBNP levels correlated significantly with changes in C-reactive protein values and leukocyte counts, but did not follow changes in pulmonary artery occlusion pressures. The results suggest that elevated levels of natriuretic peptides do not necessarily imply a low cardiac output state and/or elevated left ventricular filling pressures. In study 3 twelve patients with acute heart failure and nine patients with severe sepsis or septic shock had simultaneous haemodynamic measurements by the pulmonary artery catheter and the single indicator transpulmonary thermodilution (PiCCO) technique. The cardiac function index correlated with the left ventricular stroke work index, and a low cardiac function index identified cardiac dysfunction in patients with sepsis. As described in the review article, sepsis-related changes in circulating volume and vessel tone inevitably affect cardiac performance. Although the coronary circulation during sepsis is maintained or even increased, alterations in the microcirculation are likely. Mitochondrial dysfunction, another feature of sepsis-induced organ dysfunction, will also place the cardiomyocytes at risk of adenosine triphosphate depletion. However, clinical studies have demonstrated that myocardial cell death is rare and that cardiac function is fully reversible in survivors. Hence, functional rather than structural changes seem to be responsible for intrinsic myocardial depression during sepsis. The underlying mechanisms include down-regulation of betaadrenergic receptors, depressed post-receptor signaling pathways, impaired calcium liberation from the sarcoplasmic reticulum, and impaired electromechanical coupling at the myofibrillar level. Most, if not all, of these changes are regulated by cytokines and nitric oxide. Integrative studies are needed to distinguish the hierarchy of the various mechanisms underlying septic cardiac dysfunction. As many of these changes are related to severe inflammation and not to infection per se, a better understanding of septic myocardial dysfunction may be usefully extended to other systemic inflammatory conditions encountered in the critically ill. Myocardial depression may be arguably viewed as an adaptive event by reducing energy expenditure in a situation when energy generation is limited, thereby preventing activation of cell death pathways and potentially allowing full functional recovery. Analogies can be drawn to ischemia-induced hibernation, a wellrecognized phenomenon in patients with ischemic heart disease. In view of these adaptive and protective mechanisms, current treatment guidelines must be challenged and new algorithms proposed. Future studies are needed to test novel cardioprotective strategies (including the use of beta-blockers, levosimendan or ivabradine) in patients with severe sepsis and septic shock.

Abstract

Sepsis, severe sepsis and septic shock represent increasingly grave stages of the systemic inflammatory response to severe infection. Affected patients have a high mortality and morbidity, predominantly as a consequence of multiple organ failure. Cardiac dysfunction with impaired left-ventricular ejection fraction is a well-described manifestation of this syndrome and can be diagnosed in up to 60% of patients with septic shock. The three original articles of this cumulative habilitation describe the cardiac and haemodynamic alterations in septic patients. The review article summarises underlying mechanisms of sepsis-induced cardiac dysfunction. In study 1, B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) levels were measured in 24 patients with severe sepsis or septic shock and 51 patients with acute heart failure. We showed, that in patients with severe sepsis or septic shock, BNP and NT-proBNP values were highly elevated and, despite significant haemodynamic differences, comparable with those found in acute heart failure patients. This supported previous studies, which attributed elevated BNP levels to sepsis-induced myocardial dysfunction. Twelve haemodyamic unstable patients, all monitored with a pulmonary artery catheter, were included in study 2. Despite significant differences in cardiac index and troponin T plasma level, BNP and NTproBNP levels did not differ significantly between the patients with sepsis and acute heart failure. Within patient, changes in BNP and NT-proBNP levels correlated significantly with changes in C-reactive protein values and leukocyte counts, but did not follow changes in pulmonary artery occlusion pressures. The results suggest that elevated levels of natriuretic peptides do not necessarily imply a low cardiac output state and/or elevated left ventricular filling pressures. In study 3 twelve patients with acute heart failure and nine patients with severe sepsis or septic shock had simultaneous haemodynamic measurements by the pulmonary artery catheter and the single indicator transpulmonary thermodilution (PiCCO) technique. The cardiac function index correlated with the left ventricular stroke work index, and a low cardiac function index identified cardiac dysfunction in patients with sepsis. As described in the review article, sepsis-related changes in circulating volume and vessel tone inevitably affect cardiac performance. Although the coronary circulation during sepsis is maintained or even increased, alterations in the microcirculation are likely. Mitochondrial dysfunction, another feature of sepsis-induced organ dysfunction, will also place the cardiomyocytes at risk of adenosine triphosphate depletion. However, clinical studies have demonstrated that myocardial cell death is rare and that cardiac function is fully reversible in survivors. Hence, functional rather than structural changes seem to be responsible for intrinsic myocardial depression during sepsis. The underlying mechanisms include down-regulation of betaadrenergic receptors, depressed post-receptor signaling pathways, impaired calcium liberation from the sarcoplasmic reticulum, and impaired electromechanical coupling at the myofibrillar level. Most, if not all, of these changes are regulated by cytokines and nitric oxide. Integrative studies are needed to distinguish the hierarchy of the various mechanisms underlying septic cardiac dysfunction. As many of these changes are related to severe inflammation and not to infection per se, a better understanding of septic myocardial dysfunction may be usefully extended to other systemic inflammatory conditions encountered in the critically ill. Myocardial depression may be arguably viewed as an adaptive event by reducing energy expenditure in a situation when energy generation is limited, thereby preventing activation of cell death pathways and potentially allowing full functional recovery. Analogies can be drawn to ischemia-induced hibernation, a wellrecognized phenomenon in patients with ischemic heart disease. In view of these adaptive and protective mechanisms, current treatment guidelines must be challenged and new algorithms proposed. Future studies are needed to test novel cardioprotective strategies (including the use of beta-blockers, levosimendan or ivabradine) in patients with severe sepsis and septic shock.

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